SXR as a Therapeutic Target in Drug Resistant Cancer

描述：（申请人提供） 类固醇和外源性生物素受体（SXR）是最近鉴定的一个成员， 蛋白质的核受体家族; SXR与RXR异二聚化， 激活基因转录。已知激活SXR的配体包括几种 类固醇如雌二醇、孕酮和皮质酮，以及药物如 利福平、克霉唑和硝苯地平。在这方面工作的基本原理 建议是基于我们的观察：a）紫杉醇，而不是泰索帝，是一种 SXR的有效激活剂; B）SXR是MDR 1的转录激活剂， 细胞色素P450 3A 4（CYP 3A 4）在人体组织中的表达; c）处理的细胞 与已知的SXR激活剂，如紫杉醇，表现出快速诱导Pgp 和CYP 3A 4表达，导致 化疗药物外排和代谢失活;和 CYP 3A 4在一系列人类肿瘤中不稳定表达。我们的数据表明 SXR可能是导致多重耐药表型的部分原因 通过快速瞬时诱导药物转运所需的基因 和代谢清除率。我们假设SXR是一个重要的决定因素， 通过瞬时诱导药物治疗所需的基因， 解毒，新的化合物或策略，旨在阻止 SXR的激活可抑制耐药性的产生。在测试我们的 假设，我们将更好地了解信号通路 CYP 3A 4、MDR 1和其他耐药相关基因上游，以及 阐明这些基因通过SXR的内在诱导是否是一种 癌症治疗失败的重要机制。此外，工作 在这项提案中进行的研究将确定SXR基因表达是否升高， 相对于邻近的正常组织，如果我们的整体假设 证实，新的药物不是SXR的配体或药物， SXR的激活，将废除诱导药物的出现， SXR过度表达肿瘤患者的耐药性。

DESCRIPTION: (provided by applicant) The Steroid and Xenobiotic Receptor (SXR) is a recently-identified member of the nuclear receptor family of proteins; SXR heterodimerizes with RXR to activate gene transcription. Ligands known to activate SXR include several steroids such as estradiol, progesterone and corticosterone, and drugs such as rifampicin, clotrimazole and nifedipine. The rationale for work in this proposal is based on our observations that: a) taxol, but not taxotere, is a potent activator of SXR; b) SXR is a transcriptional activator of MDR1 and cytochrome P450 3A4 (CYP3A4) expression in human tissues; c) cells treated with known activators of SXR, such as taxol, exhibit a rapid induction of Pgp and CYP3A4 expression resulting in significantly increased rates of chemotherapeutic drug efflux and metabolic inactivation; and d) SXR, Pgp, and CYP3A4 are variably expressed in a range of human tumors. Our data suggests that SXR may be responsible in part for the multiple drug resistance phenotype through a rapid and transient induction of genes required for drug transport and metabolic clearance. We hypothesize that SXR is an important determinant of the MDR phenotype by transiently inducing the genes required for drug detoxification, and that new compounds or strategies designed to block activation of SXR may inhibit the emergence of drug resistance. In testing our hypothesis, we will gain a better understanding of the signaling pathway upstream of CYP3A4, MDR1, and other drug resistance-associated genes, and elucidate whether the inherent inducibility of these genes through SXR is an important mechanism of treatment failure in cancer. Furthermore, the work performed in this proposal will determine if SXR gene expression is elevated in human tumors relative to adjacent normal tissues. If our overall hypothesis is confirmed, new agents which are not ligands for SXR or drugs which block the activation of SXR, will abrogate the emergence of inducible drug resistance in patients with SXR-overexpressing tumors.